Neurodegenerative diseases (NDD) such as Alzheimer's disease (AD) and Parkinson's disease (PD) arise from the accelerated loss of certain populations of neurons in the brain. Parkinson's (PD) and Alzheimer's (AD) diseases usually appear sporadically without any obvious Mendelian inheritance patterns, but may show maternal biases. Although rare or uncommon inherited forms of adult NDD exist, the relevance of pathogenesis in these autosomal genetic variants to the much more commonly occurring sporadic forms is a subject of intense debate.
Accumulating evidence provides compelling support that a primary etiologic component of sporadic adult NDD relates to mitochondrial dysfunction and the resulting increased cellular oxidative stress. PD and AD brains and non-CNS tissues show reductions in mitochondrial electron transport chain (ETC) activity. When selectively amplified in cytoplasmic hybrid (“cybrid”) cell models, mitochondrial genes from PD (Swerdlow, et al, Exp Neurol 153:135–42, 1998) and AD (Swerdlow, et al, Exp Neurol 153:135–42 1997) subjects recapitulate the ETC deficits, produce increased oxidative stress and a variety of other important mitochondrial and cellular dysfunctions. The combined weight of evidence from tissue studies and cybrid models of sporadic PD and AD suggests that relief of oxidative stress, by agents capable of scavenging oxygen free radicals and protecting cells from mitochondrially generated cell death, be considered as a primary characteristic of compounds developed as neuroprotective agents for these diseases (Beal, Exp Neurol 153:135–42, 2000).
Oxidative stress has also been associated with the fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS). ALS, also known as Lou Gehrig's disease, is a progressive, fatal neurodegenerative disorder involving the motor neurons of the cortex, brain stem, and spinal cord. It is a degenerative disease of upper and lower motor neurons that produces progressive weakness of voluntary muscles, with eventual death. The onset of disease is usually in the fourth or fifth decade of life, and affected individuals succumb within 2 to 5 years of disease onset. ALS occurs in both sporadic and familial forms.
About 10% of all ALS patients are familial cases, of which 20% have mutations in the superoxide dismutase 1 (SOD 1) gene (formerly known as Cu,Zn-SOD), suggesting that an abnormally functioning Cu,Zn-SOD enzyme may play a pivotal role in the pathogenesis and progression of familial amyotrophic lateral sclerosis (FALS). It is believed that the increased generation of oxygen free radicals, especially hydroxyl radicals, by mutant SOD1, to be the initiating factor that results in the sequence of events leading to motor neuron death in FALS. This hypothesis is supported by recent reports that transfection of neuronal precursor cells with mutant SOD1 results in increased production of hydroxyl radicals and enhanced rate of cell death by apoptosis. Furthermore, applicants believe that oxidative stress is responsible motor neuron death in sporadic forms of ALS as well.
Recent research has revealed that a likely inciting event in the premature neuronal death that is associated with ALS is the presence of mutated mitochondrial genes (mitochondrial DNA, mtDNA). These mtDNA mutations lead to abnormalities in functioning of energy production pathways in mitochondria, resulting in an excessive generation of damaging oxygen derivatives known as “reactive oxygen species” (ROS), including entities called “oxygen free radicals.” When ROS production exceeds the capacity of cellular mechanisms to remove/inactivate ROS, the condition known as “oxidative stress” exists.
Oxidative stress can damage many cellular components. Work by the inventor has shown that a critical cell component damaged by oxidative stress in cell models of AD and PD is a particular mitochondrial protein complex known as the “mitochondrial transition pore complex” (MTPC). Normal activity of the MTPC is essential for the maintenance of a bioelectric potential (ΔΨ) across mitochondrial membranes, which in turn is used for mitochondrial synthesis of energy storage chemicals such as ATP. Loss of ΔΨ results in depolarization of mitochondria and initiates a cascade of biochemical reactions which ultimately result in cell death by a mechanism known as “programmed cell death” or “apoptosis.” Apoptosis mechanisms have been observed not only in AD and PD, but also in other NDD such as amyotrophic lateral sclerosis (ALS) and Huntington's disease.
Accordingly, one strategy for treating these various neurodegenerative diseases involves the administration of a neuroprotective agent. Effective neuroprotective agents for these debilitating and fatal illnesses should not only be effective in cell culture and animal models of these diseases, but must be tolerated chronically in high enough doses to achieve therapeutic levels in nervous tissues. Ideally such agents would also target cellular components involved in control of cell death pathways and interrupt disease pathophysiology.
In accordance with one embodiment of the present invention a method is provided for treating a neurodegenerative disease such as ALS. The method comprises the steps of administering pramipexole to the individual in an amount effective to reduce oxidative stress in that individual.
Pramipexole (PPX, 2-amino-4,5,6,7-tetrahydro-6-propylaminobenzathiazole) exists as two sterioisomers:

The S(−) enantiomer is a potent agonist at D2 family dopamine receptors and is extensively used in the symptomatic management of PD. The synthesis, formulation and administration of pramipexole is described in U.S. Pat. Nos. 4,843,086, 4,886,812 and 5,112,842, the disclosures of which are incorporated herein. S (−) PPX has been shown by several groups to be neuroprotective in cellular and animal models of increased oxidative stress, including MPTP toxicity to dopamine neurons (see U.S. Pat. Nos. 560,420 and 6,156,777, the disclosures of which are incorporated herein). S(−) PPX reduces oxidative stress produced by the parkinsonian neurotoxin and ETC complex I inhibitor methylpyridinium (MPP+) both in vitro and in vivo and can block opening of the mitochondrial transition pore (MTP) induced by MPP+ and other stimuli (Cassarino, et al, 1998). The lipophilic cationic structure of PPX is suggestive of the possibility that concentration into mitochondria across ΔΨM, in combination with its low reduction potential (320 mV), may account for these desirable neuroprotective properties.
Dosing with S(−) PPX is limited in humans by its potent dopamine agonist properties and will restrict achievable brain drug levels. Because the R(+) enantiomer of PPX has very little dopamine agonist activity (Schneider and Mierau, J Med Chem 30:494–498,1987) but may retain the desirable molecular/antioxidant properties of S(−) PPX, this compound is suggested herein as having utility as an effective inhibitor of the activation of cell death cascades and loss of viability that occurs in neurodegenerative diseases.